Therapeutic discovery for cholangiocellular carcinoma

Projektinformationen

CANDY

ID Finanzhilfevereinbarung: 101069276

DOI

10.3030/101069276

Projekt abgeschlossen

EK-Unterschriftsdatum 14 April 2022

Startdatum 1 August 2022

Enddatum 31 Januar 2024

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

Keine Daten

EU-Beitrag

€ 150 000,00

Koordiniert durch

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - CANDY (Therapeutic discovery for cholangiocellular carcinoma)

Berichtszeitraum: 2022-08-01 bis 2024-01-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Cholangiocarcinoma (CCA) is one of the deadliest cancers comprising a heterogeneous cluster of malignancies that are distinct to hepatocellular carcinoma (HCC) and that can emerge at any point in the biliary tree. CCA is mostly diagnosed very late resulting in aggressive disease progression, poor treatment response, and dismal prognosis with a median survival of less than 2 years. Curative hepatic resection is an option in a minority of patients with frequent recurrence. For most patients, diagnosis will occur when the disease is already too advanced, and the only options are chemotherapies or palliative care. Current standard-of-care for CCA is unsatisfactory with very limited efficacy and adverse effects. Recently approved second-line therapeutics (e.g. Pemigatinib, a fibroblast growth factor receptor inhibitor, and Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) mutant inhibitor) can improve outcome. However, these are only suited to a small subset of CCA patients and have significant adverse effects. Thus, there is a major unmet medical need for novel therapeutic strategies to improve patient outcome. Claudin-1 (CLDN1) is a transmembrane protein expressed in tight junctions, but exposed at the cell surface on cancer epithelial cells. The aim of CANDY was to investigate the CLDN1 as a therapeutic target in preclinical proof-of-concept studies based on monoclonal antibodies and models characterized or established within ERC FIBCAN.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Proof-of-concept studies were performed in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse as well as patient CCA organoid models. Targeting exposed CLDN1 demonstrated a robust anti-tumoral effect across intra-and extra-hepatic CCA mouse models, with a significant inhibition of metastatic disease. Functional studies in patient-derived CCA organoids led to decreased cellular viability and altered cancer cell plasticity and fate. Mechanistically, our proposed treatment suppressed gene expression of pathways mediating proliferation, stemness and EMT by inhibiting oncogenic signaling.
A publication presenting these results is in preparation.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

These results demonstrate that Claudin-1 is a CCA driver and therapeutic target. The proof-of-concept studies in patient-derived models pave the way for the clinical development of a novel treatment to improve the outcomes of patients with advanced CCA. Moreover, the understanding of the role of Claudin-1 and its mechanism of action paves the way towards the exploration of similar treatments in other malignancies.